I. Field of the Invention
The present invention relates generally to the fields of biology, chemistry and medicine. More particularly, it concerns derivatives of avicin D, and methods of making and using thereof, including for the treatment of cancer.
II. Description of Related Art
Avicins, a family of plant triterpene electrophiles, have been reported to trigger apoptosis-associated tumor cell death, and suppress chemical-induced carcinogenesis by their anti-inflammatory, anti-mutagenic, and antioxidant properties.
Avicins can be isolated from the Australian desert tree (Leguminosae) Acacia victoriae. The extraction and purification of avicins from the ground pods of Acacia victoriae is described in detail by U.S. Pat. No. 6,444,233, which is incorporated herein by reference. Using induction of cell cytotoxicity as a screen, two compounds, avicin D and avicin G, were identified as having significant activity.
Avicin D has been shown to inhibit NF-κB and activate NF-E2-related factor 2 (Nrf2) respectively, both in a redox-dependant manner, accounting for its anti-inflammatory and antioxidant properties. The ability of avicins to interact with, and modify cysteine residues was first demonstrated in a bacterial system with OxyR as a target, wherein it was demonstrated that the distal portion of the avicin side chain formed a reversible and covalent thioester bond with the critical cysteine (SH) on the OxyR molecule. This protein modification, termed avicinylation, suggested that avicins can be used induce post-translational changes in proteins to regulate their function.
Given these promising properties and the pressing need for improved therepeutics in a diverse range of indications, it is desirable to synthesize new compounds with diverse structures that may have improved biological activity profiles. Therefore, it is an object of the invention to provide derivatives of avicin D, and methods of making and using these. For example, recent studies have shown the existence of self renewing, stem-like cells within tumors, now called cancer stem cells (CSCs). See Reya et al., 2001, which is incorporated herein by reference. CSCs are resistant to most anti cancer treatments and possess the ability to seed new tumors. Therefore agents that can target and kill these CSCs are actively sought after for more effective anti-cancer treatment.